Recent findings indicate that the PrP genotype and the PrPSc type have a major influence on the disease phenotype in both sporadic and familial human prion diseases. Prion diseases are unique transmissible neurodegenerative diseases that have diverse phenotypes and can be familial, sporadic, or acquired by infection. These data indicate that MM2-thalamic sCJD is caused by a prion strain distinct from the other sCJD subtypes including the MM2-cortical form. The affected mice showed deposition of type 2A PrPSc, a scenario that is unprecedented in this mouse line. Challenge of transgenic mice expressing 129MM human PrP showed that MM2-thalamic sporadic CJD (sCJD) was able to transmit the disease, at variance with MM2-cortical sCJD. Western blot analysis showed the presence of type 2A PrPSc. Main neuropathological features were diffuse, synaptic PrP immunoreactivity in the cerebral cortex and severe neuronal loss and gliosis in the thalamus and olivary nucleus. We observed two young patients with MM2-thalamic CJD. The rare 129MM CJD patients with type 2 PrPSc are further subdivided in a cortical and a thalamic form also indicated as sporadic fatal insomnia. Approximately 95% of the sporadic 129MM CJD patients are characterized by cerebral deposition of type 1 PrPSc and correspond to the classic clinical CJD phenotype. In Creutzfeldt–Jakob disease (CJD), molecular typing based on the size of the protease resistant core of the disease-associated prion protein (PrPSc) and the M/V polymorphism at codon 129 of the PRNP gene correlates with the clinico-pathologic subtypes.

In this manuscript, we present an overview of the current applications and future perspectives of RT-QuIC in the field of sCJD diagnosis. This discovery represents an important step forward for the clinical diagnosis of sCJD. Thanks to the advent of the ultrasensitive Real-Time Quaking-Induced Conversion (RT-QuIC) assay, PrPSc was found in several peripheral tissues of sCJD patients, sometimes even before the clinical onset of the disease. Clinical diagnosis of sCJD is very challenging and is based on the combination of several clinical, instrumental and laboratory tests representing surrogate disease biomarkers. Definitive sCJD diagnosis requires brain analysis with the aim of identifying intracerebral accumulation of PrPSc which currently represents the only reliable biomarker of the disease.

At least six different sCJD phenotypes have been described and each of them is thought to be caused by a peculiar PrPSc strain. The origin of this variability lies in the aberrant structures acquired by PrPSc. The disease is highly heterogeneous from a clinical and neuropathological point of view. Once formed, PrPSc interacts with the normally folded PrPC coercing it to undergo similar structural rearrangement. The disease is caused by a proteinaceous infectious agent, named prion (or PrPSc), which arises from the conformational conversion of the cellular prion protein (PrPC). Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare and fatal neurodegenerative disorder with an incidence of 1.5 to 2 cases per million population/year. Video‐polysomnography, FDG‐PET, and especially CSF prion RT‐QuIC and NfL constitute the most promising supportive diagnostic tests in vivo. The combination of psychiatric and/or sleep‐related symptoms with oculomotor abnormalities represent early peculiar clinical feature of sFI to be valued in the differential diagnosis. SFI is a disease of young or middle‐aged adults, which is difficult to reconcile with the hypothesis of a spontaneous etiology related to stochastic, age‐related, PrP misfolding. Molecular analyses revealed PrPSc type 2 and methionine homozygosity at PRNP codon 129 in all cases. EEG and MRI showed non‐specific findings, whereas FDG‐PET demonstrated a profound bilateral thalamic hypometabolism in 71% of cases. CSF levels of proteins 14‐3‐3 and t‐tau were unrevealing, the concentration of neurofilament light protein (NfL) was more consistently increased, and the real‐time quaking‐induced conversion assay (RT‐QuIC) revealed a positive prion seeding activity in 60% of cases. In all tested patients, video‐polysomnography demonstrated a severe reduction of total sleep time and/or a disorganized sleep. Early clinical findings included psychiatric, sleep and oculomotor disturbances, followed by cognitive decline and postural instability. Mean age at onset was 43 years and mean disease duration 30 months. We undertook a detailed analysis of clinical and histopathological features, and the results of diagnostic investigations. Comprehensively describe the phenotypic spectrum of sporadic Fatal Insomnia (sFI) to facilitate diagnosis and management of this rare and peculiar prion disorder.Ī survey among major prion disease reference Centres in Europe identified 13 patients diagnosed with sFI in the past 20 years.

Fatal insomnia